Funded Studies

Timeline: 2022-2027

Funding:  National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) R01

PIs: Hannah C. Glass, MDCM, MAS, Adam L. Numis MD, and Elliott Sherr MD, PhD

Participating Sites: UCSF Benioff Children's Hospital, University of Michigan C.S. Mott Children's Hospital, Boston Children’s Hospital, Children’s Hospital of Philadelphia, Children’s Research Institute, Cincinnati Children’s Hospital Medical Center, Massachusetts General Hospital, Duke University Duke Children's Hospital

Aims

1. To carefully characterize the epilepsy phenotype of neonates with acute symptomatic seizures and develop a biorepository to bank DNA trios from subjects and families
2. To identify genetic differences among neonates with epilepsy after acute neonatal seizures, compared with those who do not develop epilepsy

Key Findings

Stay tuned!

Timeline: 2020-2024

Funding: National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) R01

PIs: Hannah C. Glass, MDCM, MAS and Renée A. Shellhaas, MD, MS

Participating Sites: UCSF Benioff Children's Hospital, University of Michigan C.S. Mott Children's Hospital, Boston Children’s Hospital, Children’s Hospital of Philadelphia, Children’s National Medical Center, Cincinnati Children’s Hospital Medical Center, Massachusetts General Hospital, Duke University Duke Children's Hospital, Stanford University Lucile Packard Children's Hospital

Aims

1a: Identify predictors of disability in children with prior acute symptomatic neonatal seizures

1b: Examine risk factors for decline in adaptive behavior in children with prior acute symptomatic neonatal seizures

2a: Determine whether parent well-being alters the risk for disability among children with prior acute symptomatic neonatal seizures

2b: Determine whether parent well-being alters the adaptive behavior trajectory in children with prior acute symptomatic neonatal seizures

3. Build robust risk prediction models for childhood disability after neonatal seizures

Key Findings

Stay tuned!

Publications

1. Shellhaas RA, Wusthoff CJ, Numis AL, Chu CJ, Massey SL, Abend NS, Soul JS, Chang T, Lemmon ME, Thomas C, McNamara NA, Guillet R, Franck LS, Sturza J, McCulloch CE, Glass HC. Early-life epilepsy after acute symptomatic neonatal seizures: A prospective multicenter study. Epilepsia. 2021 Aug;62(8):1871-1882. doi: 10.1111/epi.16978. Epub 2021 Jul 2. PMID: 34212365. https://onlinelibrary.wiley.com/doi/epdf/10.1111/epi.16978

2. Glass HC, Soul JS, Chang T, et al. Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures. JAMA Neurol. 2021;78(7):817–825. doi:10.1001/jamaneurol.2021.1437 https://jamanetwork.com/journals/jamaneurology/fullarticle/2780420

Timeline: 2019-2023

Funding: National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) K23

PI: Adam L. Numis, MD

Participating Sites: UCSF Benioff Children's Hospital, University of Michigan C.S. Mott Children's Hospital, Boston Children's Hospital

Aims

1. To cross-sectionally evaluate the association of plasma cytokine levels with acute symptomatic seizure severity in neonates
2. To longitudinally investigate the association of plasma cytokine levels in neonates with acute symptomatic seizures with subsequent development of post-neonatal epilepsy
3. To correlate plasma microRNA (miRNA) expression profiles with (a) cytokine levels in neonates with and without acute symptomatic seizures, and (b) the development of PNE

Key Findings

Stay tuned!

Publications

Stay tuned!

Timeline: 2012-2015

Funding: Pediatric Epilepsy Research Foundation (PERF)

PI: Hannah C. Glass, MDCM, MAS

Participating sites: UCSF Benioff Children's Hospital, University of Michigan C.S. Mott Children's Hospital, Brigham and Women’s Hospital, Children’s Hospital Boston, Children’s Hospital of Philadelphia, Children’s National Medical Center, Massachusetts General Hospital, Stanford University Lucile Packard Children’s Hospital

Aims

1. To develop infrastructure and establish a multi-center registry of neonates with seizures
2. To identify the etiologies of clinical and electrographic (EEG) neonatal seizures
3. To identify current practices for medical management of neonatal seizures
4. To determine whether differences in management affect short-term outcomes

Key Findings

1. The most common causes of seizures in the neonatal period are hypoxic-ischemic encephalopathy (HIE)/neonatal encephalopathy, ischemic stroke, and intracranial hemorrhage.
2. Neonatal onset epilepsy represents an important minority of seizures in the neonatal period (10-15% of neonatal seizures) and genetic testing has a high yield when no acute cause of seizures is found.
3. High seizure burden is associated with short and long term adverse outcomes and mortality.
4. Preterm newborns are more likely to have subclinical seizures.
5. Approximately 2/3 of neonates require additional doses of anti-seizure medications for ongoing seizures. Children with high seizure burden, no hypothermia therapy, and abnormal EEG background are more likely to have ongoing seizures after the first dose of anti-seizure medicine.
6. While initial treatment of acute symptomatic seizures is uniform across our sites (>90% receive phenobarbital first line), duration of therapy is highly variable. Three quarters were maintained on anti-seizure medications at the time of discharge home, however the range across sites was 4% to 91%, indicating highly variable treatment practice.

Publications

1: Glass HC, Shellhaas RA, Wusthoff CJ, Chang T, Abend NS, Chu CJ, Cilio MR, Glidden DV, Bonifacio SL, Massey S, Tsuchida TN, Silverstein FS, Soul JS; Neonatal Seizure Registry Study Group. Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. J Pediatr. 2016 Jul;174:98-103.e1. doi: 10.1016/j.jpeds.2016.03.035. Epub 2016 Apr 19. PMID: 27106855; PMCID: PMC4925241. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925241/pdf/nihms780204.pdf

2: Shellhaas RA, Chang T, Wusthoff CJ, Soul JS, Massey SL, Chu CJ, Cilio MR, Bonifacio SL, Abend NS, Tsuchida TN, Glass HC; Neonatal Seizure Registry Study Group. Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study. J Pediatr. 2017 Feb;181:298-301.e1. doi: 10.1016/j.jpeds.2016.10.039. Epub 2016 Nov 7. PMID: 27829512; PMCID: PMC5322461. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322461/pdf/nihms849412.pdf

3: Glass HC, Shellhaas RA, Tsuchida TN, Chang T, Wusthoff CJ, Chu CJ, Cilio MR, Bonifacio SL, Massey SL, Abend NS, Soul JS; Neonatal Seizure Registry study group. Seizures in Preterm Neonates: A Multicenter Observational Cohort Study. Pediatr Neurol. 2017 Jul;72:19-24. doi: 10.1016/j.pediatrneurol.2017.04.016. Epub 2017 Apr 20. PMID: 28558955; PMCID: PMC5863228. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863228/pdf/nihms949117.pdf

4: Shellhaas RA, Wusthoff CJ, Tsuchida TN, Glass HC, Chu CJ, Massey SL, Soul JS, Wiwattanadittakun N, Abend NS, Cilio MR; Neonatal Seizure Registry. Profile of neonatal epilepsies: Characteristics of a prospective US cohort. Neurology. 2017 Aug 29;89(9):893-899. doi: 10.1212/WNL.0000000000004284. Epub 2017 Jul 21. PMID: 28733343; PMCID: PMC5577964. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577964/pdf/NEUROLOGY2016771188.pdf

5: Glass HC, Soul JS, Chu CJ, Massey SL, Wusthoff CJ, Chang T, Cilio MR, Bonifacio SL, Abend NS, Thomas C, Lemmon M, McCulloch CE, Shellhaas RA; Neonatal Seizure Registry study group. Response to antiseizure medications in neonates with acute symptomatic seizures. Epilepsia. 2019 Mar;60(3):e20-e24. doi: 10.1111/epi.14671. Epub 2019 Feb 20. PMID: 30790268; PMCID: PMC6443409. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443409/pdf/nihms-1019981.pdf

Timeline: 2015-2020

Funding: Patient Centered Outcomes Research Institute (PCORI)

PIs: Renée A. Shellhaas, MD, MS and Hannah C. Glass, MDCM, MAS

Participating sites: University of Michigan C.S. Mott Children's Hospital, UCSF Benioff Children's Hospital, Boston Children’s Hospital, Children’s Hospital of Philadelphia, Children’s National Medical Center, Cincinnati Children’s Hospital Medical Center, Massachusetts General Hospital, Duke University Duke Children's Hospital, Stanford University Lucile Packard Children's Hospital

Aims

1. To determine whether short versus prolonged phenobarbital treatment affects (a) neurodevelopmental outcome, and (b) incidence of epilepsy at ages 12-months, 18-months, and 24-months
2. To determine whether duration of phenobarbital treatment during the NICU admission affects length of hospital stay among neonates with acute symptomatic seizures – a factor highlighted by stakeholders as important for family well-being
3. To determine whether short versus prolonged treatment affects parent and family well-being

Key Findings

1. Question: Is it safe to discontinue anti-seizure medication (ASM) after resolution of acute symptomatic neonatal seizures and prior to discharge from the hospital?
2. Findings: Prospective, multi-center cohort of 282 children with neonatal seizures, 64% maintained on ASM at hospital discharge showing no difference in functional neurodevelopment (primary outcome, results meeting a priori non inferiority limit) or epilepsy. Thirteen percent developed epilepsy; early onset epilepsy (<4 months) occurred in spite of maintained ASMs and >1/3 of these children had infantile spasms, a seizure type that does not respond to ASMs used for acute symptomatic neonatal seizures.
3. Meaning: These results support discontinuing ASMs for most neonates with acute symptomatic seizures prior to discharge from the hospital, an approach that will represent an evidence-based change in practice for many providers.

Publications

1: Franck LS, Shellhaas RA, Lemmon M, Sturza J, Soul JS, Chang T, Wusthoff CJ, Chu CJ, Massey SL, Abend NS, Thomas C, Rogers EE, McCulloch CE, Grant K,
Grossbauer L, Pawlowski K, Glass HC; Neonatal Seizure Registry study group. Associations between Infant and Parent Characteristics and Measures of Family
Well-Being in Neonates with Seizures: A Cohort Study. J Pediatr. 2020 Jun;221:64-71.e4. doi: 10.1016/j.jpeds.2020.02.024. PMID: 32446494. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336525/pdf/nihms-1602881.pdf

2: Lemmon M, Glass H, Shellhaas RA, Barks MC, Bailey B, Grant K, Grossbauer L, Pawlowski K, Wusthoff CJ, Chang T, Soul J, Chu CJ, Thomas C, Massey SL, Abend NS, Rogers EE, Franck LS; Neonatal Seizure Registry. Parent experience of caring for neonates with seizures. Arch Dis Child Fetal Neonatal Ed. 2020 Nov;105(6):634-639. doi: 10.1136/archdischild-2019-318612. Epub 2020 Jun 5. PMID: 32503792; PMCID: PMC7581607. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581607/pdf/nihms-1602331.pdf

3. Shellhaas RA, Soul JS, Chang T, et al. (2021). Looking at the Effect of Treatment Duration for Newborn Infants Who Have Seizures. Patient-Centered Outcomes Research Institute (PCORI). https://doi.org/10.25302/07.2021.CER.150731187. https://www.pcori.org/sites/default/files/PCORI-ShellhaasGlass374-English-Abstract.pdf

4. Glass HC, Soul JS, Chang T, et al. Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures. JAMA Neurol. 2021;78(7):817–825. doi:10.1001/jamaneurol.2021.1437 https://jamanetwork.com/journals/jamaneurology/fullarticle/2780420

5. Lemmon ME, Glass HC, Shellhaas RA, Barks MC, Bansal S, Annis D, Guerriero JL, Pilon B, Wusthoff CJ, Chang T, Soul JS, Chu CJ, Thomas C, Massey SL, Abend NS, Rau S, Rogers EE, Franck LS, on behalf of the Neonatal Seizure Registry, Family-centered care for children and families impacted by neonatal seizures: Advice from parents, Pediatric Neurology (2021), doi: https://doi.org/10.1016/j.pediatrneurol.2021.07.013. https://www.sciencedirect.com/science/article/pii/S0887899421001545

Timeline: 2017-2019

Funding: Pediatric Epilepsy Research Foundation ® (PERF™)

PIs: Renée A. Shellhaas, MD, MS and Hannah C. Glass, MDCM, MAS

Participating Sites: University of Michigan C.S. Mott Children's Hospital, UCSF Benioff Children's Hospital, Boston Children’s Hospital, Children’s Hospital of Philadelphia, Children’s National Medical Center, Cincinnati Children’s Hospital Medical Center, Massachusetts General Hospital, Duke University Duke Children's Hospital

Aims

1. To define the association between (a) neonatal EEG background patterns and (b) electrographic status epilepticus and risk of infantile spasms
2. To examine the association between injury detected on neonatal brain MRI and risk of infantile spasms
3. To develop a robust risk prediction model for infantile spasms based on neonatal clinical, EEG and MRI data

Key Findings

1. Survivors of neonatal seizures are at risk for infantile spasms (IS); individualized risk prediction could improve time to diagnosis and treatment.
2. Three risk factors predicted IS: (a) severely abnormal EEG or ≥3 days with seizures recorded on EEG, (b) deep gray or brainstem injury on MRI, and (c) abnormal tone on discharge exam.
3. The stratified risk of IS was: no factors 0% (0/82,95% confidence interval [CI] 0%-4%), one or two factors 4% (4/108, 95% CI 1%-9%), and all three factors 57% (8/14, 95% CI 29%-83%).
4. IS risk after acute symptomatic neonatal seizures can be stratified using commonly available clinical data.

Publications

1: Glass, H. C., Grinspan, Z. M., Li, Y., McNamara, N. A., Chang, T., Chu, C. J., ... & McCulloch, C. E. (2020). Risk for infantile spasms after acute symptomatic neonatal seizures. Epilepsia. https://onlinelibrary.wiley.com/doi/epdf/10.1111/epi.16749

Timeline: 2018-2019

Funding: Marcus Foundation

PIs: Hannah C. Glass, MDCM, MAS, Adam L. Numis MD, and Elliott Sherr MD, PhD

Participating Sites: UCSF Benioff Children's Hospital

Aims

1. To carefully characterize the epilepsy phenotype of neonates with acute symptomatic seizures and develop a biorepository to bank DNA trios from subjects and families
2. To identify genetic differences among neonates with epilepsy after acute neonatal seizures, compared with those who do not develop epilepsy

Key Findings

1. We performed whole exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures.
2. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy associated genes compared to those without post-neonatal epilepsy.
3. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

Publications

1. Numis AL, da Gente G, Sherr EH, Glass HC. Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures. Pediatr Res. 2021 Apr 12. doi: 10.1038/s41390-021-01509-3. Epub ahead of print. PMID: 33846556. https://www.nature.com/articles/s41390-021-01509-3.pdf